Steroids in acute liver failure? To the Editor: DiPaola et al1 present the diagnostic and management difficulties in a 2-year-old patient who developed acute liver failure (ALF) and hemophagocytic lymphohistiocytosis (HLH). She died of overwhelming adenovirus infection approximately 5 months after an emergency liver transplant and 80 days after rescue allogeneic stem cell transplantation. They highlight pancytopenia, evolving bone marrow aspirate findings, and high soluble interleukin-2 receptor levels—all highly suggestive of HLH, and the ongoing immunoparesis probably contributing to the fatal outcome. The authors conclude that early high-dose steroids should be considered for all infants with ALF and high soluble interleukin-2 receptor levels in order to abrogate the observed proinflammatory immune activation.2 They point out that infection studies should be negative although their availability in an acute clinical setting is time-consuming and often retrospective. Their broad recommendation for the steroid use could potentially be harmful for the most common form of pediatric ALF—the indeterminate one. The complex immunological events in ALF are incompletely understood.3 It is possible that in sepsis, which frequently accompanies ALF, an initial “cytokine storm” is followed by a compensatory anti-inflammatory response syndrome, which appears critical for survival.4 One study suggested that higher levels of anti-inflammatory cytokine interleukin-10 predicted a poor outcome in adults with ALF.5 A nonselective approach for a high-dose steroid administration to all critically ill children with suspected indeterminate ALF could potentially lead to an increased complication rate, except for a small proportion who could indeed have the HLH syndrome. The long-standing clinical experience is that the empirical steroids do not improve the

outcome in non-immune mediated ALF.6 However, no effort should be spared to promptly investigate for less common causes of pediatric ALF, such as mitochondrial cytopathies, perforin/granzyme B disorders, fatty acid oxidation defects, lysosomal acid lipase deficiency, or disseminated viral infection, where liver transplant may not always be the optimal treatment.

Nedim Hadzic, MD Anil Dhawan, MD Pediatric Center for Hepatology, Gastroenterology, and Nutrition King’s College Hospital London, United Kingdom http://dx.doi.org/10.1016/j.jpeds.2014.03.062

References 1. Dipaola F, Grimley M, Bucuvalas J. Pediatric liver failure and immune dysregulation. J Pediatr 2014;2:407-9. 2. Bucuvalas J, Filipovich L, Yazigi N, Narkewicz MR, Ng V, Belle SH, et al. Immunophenotype predicts outcome in pediatric acute liver failure. J Pediatr Gastroenterol Nutr 2013;56:311-5. 3. Azhar N, Ziraldo C, Barclay D, Rudnick DA, Squires RH, Vodovotz Y, Pediatric Acute Liver Failure Study Group. Analysis of serum inflammatory mediators identifies unique dynamic networks associated with death and spontaneous survival in pediatric acute liver failure. PLoS One 2013;8: e78202. 4. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112:235-43. 5. Berry PA, Antoniades CG, Hussain MJ, McPhail MJ, Bernal W, Vergani D, et al. Admission levels and early changes in serum interleukin-10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis. Liver Int 2010;30:733-40. 6. Sundaram SS, Alonso EM, Narkewicz MR, Zhang S, Squires RH. Pediatric Acute Liver Failure Study Group. Characterization and outcomes of young infants with acute liver failure. J Pediatr 2011;159:813-8.

1